Processes for the preparation of pesticidal compounds

ABSTRACT

The present application provides processes for making pesticidal compounds and compounds useful both as pesticides and in the making of pesticidal compounds.

CROSS REFERENCE TO RELATED APPLICATIONS

This Application is a divisional of U.S. application Ser. No. 14/848,383 filed on Sep. 9, 2015, which is a divisional of U.S. application Ser. No. 14/666,826 filed on Mar. 24, 2015, which is a divisional of U.S. application Ser. No. 14/517,328 filed on Oct. 17, 2014, which claims the benefit to the following U.S. Provisional Patent Applications: Ser. No. 62/043,040, filed Aug. 28, 2014; and Ser. No. 61/892,127, filed Oct. 17, 2013, the entire disclosures of these applications are hereby expressly incorporated by reference in this Application.

TECHNICAL FIELD

This application relates to efficient and economical synthetic chemical processes for the preparation of pesticidal thioether and pesticidal sulfoxides. Further, the present application relates to certain novel compounds necessary for their synthesis. It would be advantageous to produce pesticidal thioether and pesticidal sulfoxides efficiently and in high yield from commercially available starting materials.

DETAILED DESCRIPTION

The following definitions apply to the terms as used throughout this specification, unless otherwise limited in specific instances.

As used herein, the term “alkyl” denotes branched or unbranched hydrocarbon chains.

As used herein, the term “alkynyl” denotes branched or unbranched hydrocarbon chains having at least one C≡C.

Unless otherwise indicated, the term “cycloalkyl” as employed herein alone is a saturated cyclic hydrocarbon group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

The term “thio” as used herein as part of another group refers to a sulfur atom serving as a linker between two groups.

The term “halogen” or “halo” as used herein alone or as part of another group refers to chlorine, bromine, fluorine, and iodine.

The compounds and process of the present application are described in detail below in scheme 1.

In step a of Scheme 1, 4-nitropyrazole is halogenated and reduced to yield 3-chloro-1H-pyrazol-4-amine hydrochloride (1a). The halogenation occurs at the 3-carbon through the use of concentrated (37 weight percent) hydrochloric acid (HCl). The reduction occurs with triethylsilane (Et₃SiH) and palladium on alumina (Pd/Al₂O₃, preferably about 1 to 10 weight percent palladium on alumina, more preferably about 5 weight percent). This reaction may be conducted at a temperature from about 0° C. to about 40° C., preferably about 10° C. to about 20° C. This reaction may be conducted in a polar protic solvent, such as methanol (MeOH) or ethanol (EtOH), preferably ethanol. It was surprisingly discovered, that by utilizing about 1 equivalents to about 4 equivalents, preferably, about 2.5 equivalents to about 3.5 equivalents of triethylsilane in this step, while conducting the reaction between about 10° C. and about 20° C., gives about a 10:1 molar ratio of the desired halogenated product 3-chloro-1H-pyrazol-4-amine hydrochloride (1a)

versus the undesired product

1H-pyrazol-4-amine hydrochloride

In step b of Scheme 1, 3-chloro-1H-pyrazol-4-amine hydrochloride (1a) is reacted with between about 1 equivalent and about 2 equivalents of 3-chloropropionyl chloride in the presence of a base, preferably, metal carbonates, metal hydroxides, metal phosphates, more preferably sodium bicarbonate (NaHCO₃) to yield 3-chloro-N—(-3-chloro-1H-pyrazol-4-yl)propanamide (4a). The reaction may be conducted in a mixture of tetrahydrofuran (THF), and water. It was surprisingly discovered that a chloro substituent must be present at the 3-position for this reaction to proceed to completion and to also avoid over acylation. Described herein is a comparative example without a halogen at the 3-position that yielded the double acylated product (see “CE-1”). Further, comparative example with a bromo group at the 3-position afforded the product in a surprisingly low yield compared to the yield with the chloro group (see “CE-2”).

In step c of Scheme 1, 3-chloro-N—(-3-chloro-1H-pyrazol-4-yl)propanamide (4a) undergoes nucleophilic substitution by a thiol (HS—R¹), in the presence of an inorganic base, preferably, metal carbonates, metal hydroxides, metal phosphates, metal hydrides, more preferably, potassium hydroxide, conducted in the presence of a polar solvent, preferably methanol, wherein R¹ is selected from the group consisting of C₁-C₄-haloalkyl and C₁-C₄-alkyl-C₃-C₆-halocycloalkyl, preferably, R¹ is selected from CH₂CH₂CF₃ or CH₂(2,2-difluorocyclopropyl) to yield thioether (4b).

In step d of Scheme 1, thioether (4b) is reacted with a halopyridine, preferably, 3-bromopyridine in the presence of a copper salt, (such as copper(I) chloride (CuCl), copper(II) chloride (CuCl₂) or copper(I) iodide (CuI)), a base such as potassium phosphate (K₃PO₄), or potassium carbonate (K₂CO₃), preferably potassium carbonate, and N,N′-dimethylethane-1,2-diamine to yield amide (4c). This synthetic method is simpler and reduces the costs of starting materials over known heteroarylation methods. The process may be conducted in a polar solvent, such as, acetonitrile (MeCN), dioxane, or N,N-dimethylformamide at a temperature between about 50° C. and about 110° C., preferably between about 70° C. and about 90° C. It is preferred that the reaction mixture is stirred with heating for between 2 hours and 24 hours.

In step e of Scheme 1, pesticidal thioether (4c) is alkylated preferably with a R²—X² to yield pesticidal thioether (4d), wherein X² is a leaving group. The leaving group may be selected from halo, mesylate, or tosylate. R² is selected from C₁-C₄-alkyl, C₂-C₄-alkynyl, preferably, methyl, ethyl, and propargyl. R²—X² may be selected from methyl iodide, ethyl bromide, ethyl iodide, propargyl chloride, propargyl bromide, ethyl mesylate, propargyl mesylate, ethyl tosylate, and propargyl tosylate. The alkylation is conducted in the presence of an inorganic base, preferably, metal carbonates, metal hydroxides, metal phosphates, metal hydrides, more preferably, cesium carbonate (Cs₂CO₃), conducted in the presence of a polar solvent, preferably N,N-dimethylformamide (DMF) at temperatures from about 0° C. to about 50° C.

Alternatively, in step e of Scheme 1, the alkylation of pesticidal thioether (3b) may be conducted in the presence of a base such as sodium hydride (NaH), in the presence of a polar aprotic solvent, such as N,N-dimethylformamide, tetrahydrofuran, hexamethylphosphoramide (HMPA), dimethylsulfoxide (DMSO), N-methyl-2-pyrrolidinone (NMP), and sulfolane, at temperatures from about 0° C. to about 50° C. It has been unexpectedly discovered that the use of sulfolane as solvent promotes the alkylation reaction over the competitive retro-Michael-type elimination of the C₁-C₄-alkyl-S—R¹ unit (see “CE-3”). It has been discovered that the catalytic use of an additive, such as potassium iodide (KI) or tetrabutylammonium iodide (TBAI) decreases the time necessary for the reaction to occur to about 24 hours.

In step f of Scheme 1, thioether (4d) is oxidized with hydrogen peroxide (H₂O₂) in methanol to yield the desired pesticidal sulfoxide (4e).

EXAMPLES

The following examples are presented to better illustrate the processes of the present application.

Example 1 3-chloro-1H-pyrazol-4-amine hydrochloride (1a)

A 1000-mL, multi-neck cylindrical jacketed reactor, fitted with a mechanical stirrer, temperature probe and nitrogen (N₂) inlet, was charged with 4-nitropyrazole (50.0 g, 429 mmol) and palladium on alumina (5 wt %, 2.5 g). Ethanol (150 mL) was added, followed by a slow addition of concentrated hydrochloric acid (37 wt %, 180 mL). The reaction was cooled to 15° C., and triethylsilane (171 mL, 1072 mmol) was added slowly via addition funnel over 1 hour, while maintaining the internal temperature at 15° C. The reaction was stirred at 15° C. for 72 hours, after which the reaction mixture was filtered through a Celite® pad and the pad was rinsed with warm ethanol (40° C., 2×100 mL). The combined filtrates were separated and the aqueous layer (bottom layer) was concentrated to ˜100 mL. Acetonitrile (200 mL) was added and the resulting suspension was concentrated to ˜100 mL. Acetonitrile (200 mL) was added and the resulting suspension was concentrated to ˜100 mL. Acetonitrile (200 mL) was added and the resulting suspension was stirred at 20° C. for 1 hour and filtered. The filter cake was rinsed with acetonitrile (2×100 mL) and dried under vacuum at 20° C. to afford a white solid (˜10:1 mixture of 1a and 1H-pyrazole-4-amine, 65.5 g, 99%): ¹H NMR (400 MHz, DMSO-d₆) δ 10.52 (bs, 3H), 8.03 (s, 1H) EIMS m/z 117 ([M]⁺).

Example 2 3-chloro-N—(-3-chloro-H-pyrazol-4-yl) propanamide (4a)

A 250-mL 3-neck flask was charged with 3-chloro-1H-pyrazol-4-amine-hydrochloride (10.0 g, 64.9 mmol), tetrahydrofuran (50 mL), and water (50 mL). The resulting suspension was cooled to 5° C. and sodium bicarbonate (17.6 g, 210 mmol) was added, followed by dropwise addition of 3-chloropropanoyl chloride (7.33 g, 57.7 mmol) at <5° C. The reaction was stirred at <10° C. for 1 hour, at which point thin layer chromatography (TLC) [Eluent: 1:1 ethyl acetate (EtOAc)/hexane] analysis indicated the starting material was consumed and the desired product was formed. It was diluted with water (50 mL) and ethyl acetate (50 mL) and the layers separated. The aqueous layer was extracted with ethyl acetate (20 mL) and the combined organic layers were concentrated to dryness to afford a pale brown solid, which was purified by flash column chromatography using ethyl acetate as eluent. The pure fractions were concentrated to afford a white solid (9.20 g, 77%): mp: 138-140° C.; ¹H NMR (400 MHz, DMSO-d₆) δ 12.91 (s, 1H), 9.68 (s, 1H), 8.03 (d, J=1.7 Hz, 1H), 3.85 (t, J=6.3 Hz, 2H), 2.85 (t, J=6.3 Hz, 2H); ¹³C NMR (101 MHz, DMSO-d₆) δ 167.52, 130.05, 123.59, 116.48, 40.75, 37.91; EIMS m/z 207 ([M]⁺).

Example 3 N-(3-chloro-1H-pyraxol-4-yl)-3-((3,3,3,trifluoropropyl)thio)propanamide (Compound 3.4)

A 100 mL, 3-neck round bottom flask was charged with 3-chloro-N-(3-chloro-1H-pyrazol-4-yl)propanamide (1.00 g, 4.81 mmol) and methanol (10 mL), potassium hydroxide (KOH, 0.324 g, 5.77 mmol) was added, followed by 3,3,3-trifluoropropane-1-thiol (0.751 g, 5.77 mmol). The mixture was heated at 50° C. for 4 hours, at which point thin layer chromatography analysis [Eluent: ethyl acetate] indicated that the reaction was complete to give exclusively a new product. It was cooled to 20° C. and diluted with water (20 mL) and ethyl acetate (20 ml.). The layers were separated and the aqueous layer was extracted with ethyl acetate (20 mL). The organic layers were combined and dried over sodium sulfate (Na₂SO₄) and concentrated to dryness to afford a light yellow oil, which was purified by flash column chromatography using 40% ethyl acetate/hexanes as eluent to afford a white solid after concentration (1.02 g, 70%): mp 83-85° C.; ¹H NMR (400 MHz, DMSO-d₆) δ 12.90 (s, 1H), 9.59 (s, 1H), 8.02 (s, 1H), 2.82 (t, J=7.2 Hz, 2H), 2.76-2.69 (m, 2H), 2.66 (t, J=7.1 Hz, 2H), 2.62-2.48 (m, 2H); ¹³C NMR (101 MHz, DMSO-d₆) δ 168.97, 129.95, 126.60 (q, J=277.4 Hz), 123.42, 116.60, 35.23, 33.45 (q, J=27.3 Hz), 26.85, 23.03 (q, J=3.4 Hz); EIMS m/z 301 ([M]+).

Example 4 N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-3-((3,3,3-trifluoropropyl)thio)propanamide (Compound 4.4)

A 100 mL, 3-neck round bottom flask was charged with copper(I) iodide (0.343 g, 1.80 mmol), acetonitrile (50 mL), N,N′-dimethylethane-1,2-diamine (0.318 g, 3.61 mmol), N-(3-chloro-1H-pyrazol-4-yl)-3-((3,3,3-trifluoropropyl)thio)propanamide (2.72 g, 9.02 mmol), potassium carbonate (2.49 g, 18.0) and 3-bromopyridine (1.71 g, 10.8 mmol). The mixture was purged with nitrogen three times and heated to 80° C. for 4 hours, at which point thin layer chromatography analysis [Eluent: ethyl acetate] indicated that only a trace of starting material remained. The mixture was filtered through a Celite® pad and the pad was rinsed with acetonitrile (20 mL). The filtrates were concentrated to dryness and the residue was purified by flash column chromatography using 0-100% ethyl acetate/hexanes as eluent. The fractions containing pure product were concentrated to dryness and further dried under vacuum to afford a white solid (1.82 g, 53%): mp 99-102° C.; ¹H NMR (400 MHz, DMSO-d₆) δ 9.92 (s, 1H), 9.05 (d, J=2.7 Hz, 1H), 8.86 (s, 1H), 8.54 (dd, J=4.5, 1.4 Hz, 1H), 8.21 (ddd, J=8.4, 2.7, 1.4 Hz, 1H), 7.54 (dd, J=8.4, 4.7 Hz, 1H), 2.86 (t, J=7.3 Hz, 2H), 2.74 (td, J=6.5, 5.6, 4.2 Hz, 4H), 2.59 (ddd, J=11.7, 9.7, 7.4 Hz, 2H); ¹³C NMR (101 MHz, DMSO-d₆) δ 169.32, 147.49, 139.44, 135.47, 133.40, 126.60 (q, J=296 Hz), 125.49, 124.23, 122.30, 120.00, 35.18, 33.42 (q, J=27.2 Hz), 26.77, 23.05 (q, J=3.3 Hz); EIMS m/z 378 ([M]⁺).

Example 5 N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-3-((3,3,3-trifluoropropyl)thio)propanamide (Compound 5.4)

A 100 mL, 3-neck round bottom flask, equipped with mechanical stirrer, temperature probe and nitrogen inlet was charged with cesium carbonate (654 mg, 2.01 mmol), N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-3-((3,3,3-trifluoropropyl)thio)propanamide (380 mg, 1.00 mmol) and N,N-dimethylformamide, (5 mL). Iodoethane (0.089 mL, 1.10 mmol) was added dropwise. The reaction was stirred at 40° C. for 2 hours, at which point thin layer chromatography analysis [((Eluent: ethyl acetate] indicated that only a trace of starting material remained. The reaction mixture was cooled to 20° C. and water (20 mL) was added. It was extracted with ethyl acetate (2×20 mL) and the combined organic layers were concentrated to dryness at <40° C. The residue was purified by flash column chromatography using 0-100% ethyl acetate/hexane as eluent. The fractions containing pure product were concentrated to dryness to afford a colorless oil (270 mg, 66%): ¹H NMR (400 MHz, DMSO-d₆) δ 9.11 (d, J=2.7 Hz, 1H), 8.97 (s, 1H), 8.60 (dd, J=4.8, 1.4 Hz, 1H), 8.24 (ddd, J=8.4, 2.8, 1.4 Hz, 1H), 7.60 (ddd, J=8.4, 4.7, 0.8 Hz, 1H), 3.62 (q, J=7.1 Hz, 2H), 2.75 (t, J=7.0 Hz, 2H), 2.66-2.57 (m, 2H), 2.57-2.44 (m, 2H), 2.41 (t, J=7.0 Hz, 2H), 1.08 (t, J=7.1 Hz, 3H); EIMS m/z 406 ([M]⁺).

Alternate synthetic route to N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-3-((3,3,3-trifluoropropyl)thio)propanamide (Compound 5.4)

To 3-neck round bottomed flask (50 mL) was added sodium hydride (60% in oil, 0.130 g, 3.28 mmol) and sulfolane (16 mL). The gray suspension was stirred for 5 minutes then N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-3-((3,3,3-trifluoropropyl)thio)propanamide (1.20 g, 3.16 mmol) dissolved in sulfolane (25 mL) was slowly added dropwise over 5 minutes. The mixture became a light gray suspension after 3 minutes and was allowed to stir for 5 minutes after which time ethyl bromide (0.800 mL, 10.7 mmol) and potassium iodide (0.120 g, 0.720 mmol) were added sequentially. The cloudy suspension was then allowed to stir at room temperature. The reaction was quenched after 6 hours by being poured drop-wise into cooled ammonium formate/acetonitrile solution (30 mL). The resulting orange colored solution was stirred and tetrahydrofuran (40 mL) was added. The mixture was assayed, using octanophenone as a standard, and found to contain (1.09 g, 85%) of the desired product with a selectivity versus the retro-Michael-like decomposition product of 97:3.

Example 6 N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-3-((3,3,3-trifluoropropyl)sulfoxo)propanamide (Compound 6.4)

N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-3-((3,3,3-trifluoropropyl)thio) propanamide (57.4 g, 141 mmol) was stirred in methanol (180 mL). To the resulting solution was added hydrogen peroxide (43.2 mL, 423 mmol) dropwise using a syringe. The solution was stirred at room temperature for 6 hours, at which point LCMS analysis indicated that the starting material was consumed. The mixture was poured into dichloromethane (CH₂Cl₂, 360 mL) and washed with aqueous sodium carbonate (Na₂CO₃). The organic layer was dried over sodium sulfate and concentrated to provide thick yellow oil. The crude product was purified by flash column chromatography using 0-10% methanol/ethyl acetate as eluent and the pure fractions were combined and concentrated to afford the desired product as an oil (42.6 g, 68%): ¹H NMR (400 MHz, DMSO-d₆) δ 9.09 (dd, J=2.8, 0.7 Hz, 1H), 8.98 (s, 1H), 8.60 (dd, J=4.7, 1.4 Hz, 1H), 8.24 (ddd, J=8.4, 2.7, 1.4 Hz, 1H), 7.60 (ddd, J=8.4, 4.7, 0.8 Hz, 1H), 3.61 (q, J=7.4, 7.0 Hz, 2H), 3.20-2.97 (m, 2H), 2.95-2.78 (m, 2H), 2.76-2.57 (m, 2H), 2.58-2.45 (m, 2H), 1.09 (t, J=7.1 Hz, 3H); ESIMS m/z 423 ([M+H]⁺).

Example PE-1 Prophetic preparation of (2,2-difluorocyclopropyl)methanethiol

To a solution of 2-(bromomethyl)-1,1-difluorocyclopropane (about 1 equivalent) in a solvent, such as methanol (at a concentration ranging from about 0.01 M to about 1 M), at temperatures between about 0° C. and about 40° C. may be added thioacetic acid (about 1 equivalent to about 2 equivalents), and a base, such as potassium carbonate (about 1 equivalent to 2 equivalents). An additional amount of a base, such as potassium carbonate (about 1 equivalent to 2 equivalents) may be added after a time ranging from about 30 minutes to 2 hours to the mixture to remove the acyl group. The reaction may be stirred until it is determined to be complete. The product may then be obtained using standard organic chemistry techniques for workup and purification.

Alternative prophetic preparation of (2,2-difluorocyclopropyl)methanethiol

To a solution of 2-(bromomethyl)-1,1-difluorocyclopropane (about 1 equivalent) in a solvent, such as methanol (at a concentration ranging from about 0.01 M to about 1 M), at temperatures between about 0° C. and about 40° C. may be added thioacetic acid (about 1 equivalent to about 2 equivalents), and a base, such as potassium carbonate (about 1 equivalent to 2 equivalents). The intermediate thioester product may then be obtained using standard organic chemistry techniques for workup and purification. To the thioester (about 1 equivalent) in a solvent, such as methanol (at a concentration ranging from about 0.01 M to about 1 M), at temperatures between about 0° C. and about 40° C. may be added a base, such as potassium carbonate (about 1 equivalent to 2 equivalents). The reaction may be stirred until it is determined to be complete. The product may then be obtained using standard organic chemistry techniques for workup and purification.

BIOLOGICAL EXAMPLES Example A Bioassays on Green Peach Aphid (“GPA”) (Myzus persicae) (MYZUPE

GPA is the most significant aphid pest of peach trees, causing decreased growth, shriveling of leaves, and the death of various tissues. It is also hazardous because it acts as a vector for the transport of plant viruses, such as potato virus Y and potato leafroll virus to members of the nightshade/potato family Solanaceae, and various mosaic viruses to many other food crops. GPA attacks such plants as broccoli, burdock, cabbage, carrot, cauliflower, daikon, eggplant, green beans, lettuce, macadamia, papaya, peppers, sweet potatoes, tomatoes, watercress and zucchini among other plants. GPA also attacks many ornamental crops such as carnations, chrysanthemum, flowering white cabbage, poinsettia and roses. GPA has developed resistance to many pesticides.

Several molecules disclosed herein were tested against GPA using procedures described below.

Cabbage seedling grown in 3-in pots, with 2-3 small (3-5 cm) true leaves, were used as test substrate. The seedlings were infested with 20-5-GPA (wingless adult and nymph stages) one day prior to chemical application. Four posts with individual seedlings were used for each treatment. Test compounds (2 mg) were dissolved in 2 mL of acetone/methanol (1:1) solvent, forming stock solutions of 1000 ppm test compound. The stock solutions were diluted 5× with 0.025% Tween 20 in water to obtain the solution at 200 ppm test compound. A hand-held aspirator-type sprayer was used for spraying a solution to both sides of the cabbage leaves until runoff. Reference plants (solvent check) were sprayed with the diluent only containing 20% by volume acetone/methanol (1:1) solvent. Treated plants were held in a holding room for three days at approximately 25° C. and ambient relative humidity (RH) prior to grading. Evaluation was conducted by counting the number of live aphids per plant under a microscope. Percent Control was measured by using Abbott's correction formula (W. S. Abbott, “A Method of Computing the Effectiveness of an Insecticide” J. Econ. Entomol 18 (1925), pp. 265-267) as follows. Corrected % Control=100*(X−Y)/X

-   -   where     -   X=No. of live aphids on solvent check plants and     -   Y=No. of live aphids on treated plants

The results are indicated in the table entitled “Table 1: GPA (MYZUPE) and sweetpotato whitefly-crawler (BEMITA) Rating Table”.

Example B Bioassays on Sweetpotato Whitefly Crawler (Bemisia tabaci) (BEMITA)

The sweetpotato whitefly, Bemisia tabaci (Gennadius), has been recorded in the United States since the late 1800s. In 1986 in Florida, Bemisia tabaci became an extreme economic pest. Whiteflies usually feed on the lower surface of their host plant leaves. From the egg hatches a minute crawler stage that moves about the leaf until it inserts its microscopic, threadlike mouthparts to feed by sucking sap from the phloem. Adults and nymphs excrete honeydew (largely plant sugars from feeding on phloem), a sticky, viscous liquid in which dark sooty molds grow. Heavy infestations of adults and their progeny can cause seedling death, or reduction in vigor and yield of older plants, due simply to sap removal. The honeydew can stick cotton lint together, making it more difficult to gin and therefore reducing its value. Sooty mold grows on honeydew-covered substrates, obscuring the leaf and reducing photosynthesis, and reducing fruit quality grade. It transmitted plant-pathogenic viruses that had never affected cultivated crops and induced plant physiological disorders, such as tomato irregular ripening and squash silverleaf disorder. Whiteflies are resistant to many formerly effective insecticides.

Cotton plants grown in 3-inch pots, with 1 small (3-5 cm) true leaf, were used at test substrate. The plants were placed in a room with whitely adults. Adults were allowed to deposit eggs for 2-3 days. After a 2-3 day egg-laying period, plants were taken from the adult whitefly room. Adults were blown off leaves using a hand-held Devilbliss sprayer (23 psi). Plants with egg infestation (100-300 eggs per plant) were placed in a holding room for 5-6 days at 82° F. and 50% RH for egg hatch and crawler stage to develop. Four cotton plants were used for each treatment. Compounds (2 mg) were dissolved in 1 mL of acetone solvent, forming stock solutions of 2000 ppm. The stock solutions were diluted 10× with 0.025% Tween 20 in water to obtain a test solution at 200 ppm. A hand-held Devilbliss sprayer was used for spraying a solution to both sides of cotton leaf until runoff. Reference plants (solvent check) were sprayed with the diluent only. Treated plants were held in a holding room for 8-9 days at approximately 82° F. and 50% RH prior to grading. Evaluation was conducted by counting the number of live nymphs per plant under a microscope. Insecticidal activity was measured by using Abbott's correction formula (see above) and presented in Table 1.

TABLE 1 GPA (MYZUPE) and sweetpotato whitefly- crawler (BEMITA) Rating Table Example Compound BEMITA MYZUPE 1a B B 4a B D Compound 3.4 B B Compound 4.4 B A Compound 5.4 A A Compound 6.4 A A % Control of Mortality Rating 80-100 A More than 0-Less than 80 B Not Tested C No activity noticed in this bioassay D

COMPARATIVE EXAMPLES Example CE-1 N-(1-acetyl-1H-pyrazol-4-yl)acetamide

A 250-mL 3-neck flask was charged with 1H-pyrazol-4-amine (5 g, 60.2 mmol) and dichloromethane (50 mL). The resulting suspension was cooled to 5° C. and triethylamine (TEA, 9.13 g, 90.0 mmol) was added, followed by acetic anhydride (Ac₂O, 7.37 g, 72.2 mmol) at <20° C. The reaction was stirred at room temperature for 18 h, at which point thin layer chromatography [Eluent: ethyl acetate] analysis indicated that the reaction was incomplete. Additional triethylamine (4.57 g, 45.0 mmol) and acetic anhydride (3.70 g, 36.0 mmol) were added and the reaction was heated at 30° C. for an additional 3 hours to give a dark solution, at which point thin layer chromatography analysis indicated that only a trace of starting material remained. The reaction mixture was purified by flash column chromatography using ethyl acetate as eluent. The fractions containing pure product were combined and concentrated to dryness to afford an off-white solid. The solid was dried under vacuum at room temperature for 18 hours (5.55 g, 55%): ¹H NMR (400 MHz, DMSO-d₆) δ 10.30 (s, 1H), 8.39 (d, J=0.7 Hz, 1H), 7.83 (d, J=0.7 Hz, 1H), 2.60 (s, 3H), 2.03 (s, 3H); EIMS m/z 167 ([M]⁺).

Example CE-2 N-(3-Bromo-1H-pyrazol-4-yl)acetamide

A 250 mL 3-neck round bottom flask was charged with 1H-pyraz-4-amine.hydrobromide (4.00 g, 24.7 mmol) and water (23 mL). To the mixture, sodium bicarbonate (8.30 g, 99.0 mmol) was added slowly over 10 minutes, followed by tetrahydrofuran (23 mL). The mixture was cooled to 5° C. and acetic anhydride (2.60 g, 25.4 mmol) was added over 30 minutes while maintaining the internal temperature at <10° C. The reaction mixture was stirred at ˜5° C. for 20 minutes, at which point ¹H NMR and UPLC analyses indicated that the starting material was consumed and the desired product as well as bis-acetylated byproduct were formed. The reaction was extracted with ethyl acetate and the organic layers were dried over magnesium sulfate (MgSO₄) and concentrated. The crude mixture was triturated with methyl tert-butylether (MTBE) to remove the bisacetylated product to afford ˜1.24 g of a white solid. ¹H NMR analysis showed it was 1:1.1 desired to undesired bisacetylated product. The solid was purified by flash column chromatography using 50-100% ethyl acetate/hexanes as eluent to afford the desired product as a white solid (380 mg, 7.5%) and the hisacetylated product as a white solid (˜800 mg): ¹H NMR (400 MHz, DMSO-d₆) δ 13.01 (s, 1H), 9.36 (s, 1H), 7.92 (s, 1H), 2.03 (s, 3H); ¹³C NMR (101 MHz, DMSO-d₆) δ 167.94, 123.93, 119.19, 119.11, 22.63; ESIMS m/z 204 ([M+H]⁺).

Example CE-3 Alkylation Versus Retro-Michael-Like Decomposition

A suspension of sodium hydride (60% in oil, 1.03 equivalent) and solvent (1 vol) was stirred for 5 minutes. N-(3-Chloro-1-(pyridin-3-yl)-H-pyrazol-4-yl)-3-((3,3,3-trifluoropropyl)thio)propanamide (1 equivalent) dissolved in solvent (2 vol) was slowly added dropwise over 5 minutes. Ethyl bromide (3.3 equivalents) and additive (0.22 equivalents) were added sequentially. The suspension was then allowed to stir at room temperature until consumption of starting material was observed. The selectivity of Compound 6.3 over the decomposition product was determined by HPLC (See Table 2).

TABLE 2 Compound 6.3: Time Decomposition Entry Additive Solvent (hours) Product 1 tetrabutyl- N,N- 24  81:19 ammonium dimethylformamide iodide 2 potassium iodide N,N- 72 94:6 dimethylformamide 3 potassium iodide N- 20 92:8 methylpyrolidinone

It should be understood that while this invention has been described herein in terms of specific embodiments set forth in detail, such embodiments are presented by way of illustration of the general principles of the invention, and the invention is not necessarily limited thereto. Certain modifications and variations in any given material, process step or chemical formula will be readily apparent to those skilled in the art without departing from the true spirit and scope of the present invention, and all such modifications and variations should be considered within the scope of the claims that follow. 

What is claimed is:
 1. A process comprising: (a) halogenating and reducing 4-nitropyrazole

with concentrated hydrochloric acid at a temperature between about 10° C. and about 20° C. with between about 1 equivalent and about 4 equivalents of triethylsilane and about 1 to 10 weight percent palladium on alumina to yield 3-chloro-1H-pyrazol-4-amine hydrochloride (1a)

(b) acylating 1(a) with 3-chloropropionyl chloride in the presence of a base to yield 3-chloro-N—(-3-chloro-1H-pyrazol-4-yl)propanamide (4a)

(c) reacting (4a) with HS—R¹ in the presence of a base wherein R¹ is selected form the group consisting of C₁-C₄ haloalkyl and C₁-C₄ alkyl-C₃-C₆ halocycloalkyl to yield pesticidal thioethers (4b),

(d) heteroarylation of (4b) with a halopyridine in the presence of a copper salt, an amine, and a base, to yield thioether (4c)

(e) alkylating a thioether (4c) with R²—X² in the presence of a base wherein R² is selected from the group consisting of C₁-C₄-alkyl and C₂-C₄-alkynyl, and wherein X² is a leaving group, to yield thioether (4d)


2. The process according to claim 1 wherein R¹ is C₁-C₄ haloalkyl.
 3. The process according to claim 1 wherein R¹ is CH₂CH₂CF₃.
 4. The process according to claim 1 wherein R¹ is C₁-C₄ alkyl-C₃-C₆ halocycloalkyl.
 5. The process according to claim 1 wherein R¹ is CH₂(2,2-difluorocyclopropyl).
 6. The process according to claim 1, wherein thioether (4d)

is prepared by alkylating thioether (4c) with R²—X²

wherein R² is selected from the group consisting of C₁-C₄-alkyl and C₂-C₄-alkynyl, wherein X² is a leaving group, in the presence of a base, in the presence of a polar aprotic solvent, and in the presence of an additive.
 7. The process of claim 1, wherein the base in step (b) is a metal carbonate, a metal hydroxide or a metal phosphate.
 8. The process of claim 1, wherein the base in step (b) is a NaHCO₃.
 9. The process of claim 1, wherein step (b) is carried out in the presence of a mixture of tetrahydrofuran and water.
 10. The process of claim 1, wherein the base in step (c) is a metal carbonate, a metal hydroxide, a metal phosphate or metal hydride.
 11. The process of claim 1, wherein the base in step (c) is potassium hydroxide.
 12. The process of claim 1, wherein step (c) is carried out in the presence of a polar solvent.
 13. The process of claim 1, wherein step (c) is carried out in the presence of methanol.
 14. The process of claim 1, wherein the halopyridine in step (d) is 3-bromopyridine.
 15. The process of claim 1, wherein the copper salt in step (d) is copper(I) chloride (CuCl), copper(II) chloride (CuCl₂) or copper(I) iodide (CuI).
 16. The process of claim 1, wherein the amine in step (d) is N,N′-dimethylethane-1,2-diamine.
 17. The process of claim 1, wherein the base in step (d) is potassium phosphate or potassium carbonate.
 18. The process of claim 1, wherein R²—X² in step (e) is selected from the group consisting of methyl iodide, ethyl bromide, ethyl iodide, propargyl chloride, propargyl bromide, ethyl mesylate, propargyl mesylate, ethyl tosylate, and propargyl tosylate.
 19. The process of claim 1, wherein base in step (e) is a metal carbonate, a metal hydroxides, a metal phosphate or metal hydride.
 20. The process of claim 1, wherein base in step (e) is cesium carbonate. 